6 research outputs found
First Evidence That Oligopyridines, α-Helix Foldamers, Inhibit Mcl-1 and Sensitize Ovarian Carcinoma Cells to Bcl-x L -Targeting Strategies
International audienceApoptosis control defects such as the deregulation of Bcl-2 family member expression are frequently involved in chemoresistance. In ovarian carcinoma, we previously demonstrated that Bcl-xL and Mcl-1 cooperate to protect cancer cells against apoptosis and their concomitant inhibition leads to massive apoptosis even in the absence of chemotherapy. Whereas Bcl-xL inhibitors are now available, Mcl-1 inhibition, required to sensitize cells to Bcl-xL-targeting strategies, remains problematic. In this context, we designed and synthesized oligopyridines potentially targeting the Mcl-1 hydrophobic pocket, evaluated their capacity to inhibit Mcl-1 in live cells, and implemented a functional screening assay to evaluate their ability to sensitize ovarian carcinoma cells to Bcl-xL-targeting strategies. We established structureâactivity relationships and focused our attention on MR29072, named Pyridoclax. Surface plasmon resonance assay demonstrated that pyridoclax directly binds to Mcl-1. Without cytotoxic activity when administered as a single agent, pyridoclax induced apoptosis in combination with Bcl-xL-targeting siRNA or with ABT-737 in ovarian, lung, and mesothelioma cancer cell
First Evidence That Oligopyridines, αâHelix Foldamers, Inhibit Mclâ1 and Sensitize Ovarian Carcinoma Cells to Bclâx<sub>L</sub>âTargeting Strategies
Apoptosis
control defects such as the deregulation of Bcl-2 family member expression
are frequently involved in chemoresistance. In ovarian carcinoma,
we previously demonstrated that Bcl-x<sub>L</sub> and Mcl-1 cooperate
to protect cancer cells against apoptosis and their concomitant inhibition
leads to massive apoptosis even in the absence of chemotherapy. Whereas
Bcl-x<sub>L</sub> inhibitors are now available, Mcl-1 inhibition,
required to sensitize cells to Bcl-x<sub>L</sub>-targeting strategies,
remains problematic. In this context, we designed and synthesized
oligopyridines potentially targeting the Mcl-1 hydrophobic pocket,
evaluated their capacity to inhibit Mcl-1 in live cells, and implemented
a functional screening assay to evaluate their ability to sensitize
ovarian carcinoma cells to Bcl-x<sub>L</sub>-targeting strategies.
We established structureâactivity relationships and focused
our attention on MR29072, named Pyridoclax. Surface plasmon resonance
assay demonstrated that pyridoclax directly binds to Mcl-1. Without
cytotoxic activity when administered as a single agent, pyridoclax
induced apoptosis in combination with Bcl-x<sub>L</sub>-targeting
siRNA or with ABT-737 in ovarian, lung, and mesothelioma cancer cells